The overall goal of this program is to understand how the interaction of antigen, under different conditions, with receptors on lymphocytes can have different outcomes. Several aspects of this problem will be considered in detail. Projects 1 and 2 will address the question of intracellular signals in lymphocytes, and their effects on the fate of the cell. Project 1 will concentrate on the effects of signals generated by various antigen complexes, project 2 will focus on the consequences of different intracellular Ca++ levels. Project 3 is also involved in the consequences of intracellular signalling, in this case in the signals transduced by CD4 interaction with Class II during recognition of superantigens by developing thymocytes and mature T cells. The fifth project will attack the question in intact animals, with studies on the effects of exposing lymphocytes to tolerizing and activating antigens at the same time. Does one signal overcome the other, and what are the consequences of this for potentially autoimmune T cells? Finally, project 4 will examine a system which may eventually contribute to all the other experimental systems used here. The investigators on this project have established conditions under which embryonic stem cells can differentiate in tissue culture into what appear to be prothymocytes. Project 4 is designed to refine this system and test its use in studies on the induction of T cells tolerance.